Systematic in silico analysis of clinically tested drugs for reducing amyloid‐beta plaque accumulation in Alzheimer's disease. Issue 9 (2nd May 2021) - Madrasi, Kumpal
Abstract: Introduction: Despite strong evidence linking amyloid beta (Aβ) to Alzheimer's disease, most clinical trials have shown no clinical efficacy for reasons that remain unclear. To understand why, we developed a quantitative systems pharmacology (QSP) model for seven therapeutics: aducanumab, crenezumab, solanezumab, bapineuzumab, elenbecestat, verubecestat, and semagacestat. Methods: Ordinary differential equations were used to model the production, transport, and aggregation of Aβ; pharmacology of the drugs; and their impact on plaque. Results: The calibrated model predicts that endogenous plaque turnover is slow, with an estimated half‐life of 2.75 years. This is likely why beta‐secretase inhibitors have a smaller effect on plaque reduction. Of the mechanisms tested, the model predicts binding to plaque and inducing antibody‐dependent cellular phagocytosis is the best approach for plaque reduction. Discussion: A QSP model can provide novel insights to clinical results. Our model explains the results of clinical trials and provides guidance for future therapeutic development.